Synthesis and Significant Cytostatic Activity of 7-Hetaryl-7-deazaadenosines

0364270 - ÚOCHB 2012 RIV US eng J - Journal Article
Bourderioux, Aurelie - Nauš, Petr - Perlíková, Pavla - Pohl, Radek - Pichová, Iva - Votruba, Ivan - Džubák, P. - Konečný, P. - Hajdúch, M. - Stray, K. M. - Wang, T. - Ray, A. S. - Feng, J. Y. - Birkuš, G. - Cihlar, T. - Hocek, Michal
Synthesis and Significant Cytostatic Activity of 7-Hetaryl-7-deazaadenosines.
Journal of Medicinal Chemistry. Roč. 54, č. 15 (2011), s. 5498-5507. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT 1M0508; GA ČR GAP207/11/0344
Grant - others:GA MŠk(CZ) LC07017
Program: LC
Institutional research plan: CEZ:AV0Z40550506
Keywords : adenosine-kinase-inhibitors * cross-coupling reactions * cytotoxic nucleoside analogs * enzyme-inhibition * ribonucleosides
Subject RIV: CC - Organic Chemistry
Impact factor: 5.248, year: 2011

A series of 7-aryl- and 7-hetaryl-7-deazaadenosines were prepared by the cross-coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes or zinc halides. Nucleosides bearing 5-membered heterocycles at the position 7 exerted potent in vitro anti-proliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model.
Permanent Link: http://hdl.handle.net/11104/0199795